tbuckley/cabot-search huggingface dataset:
Sustained <scp>Limb‐Level</scp> Loading: A Ground Reaction Force Phenotype Common to Individuals at High Risk for and Those With Knee Osteoarthritis
Authors: Elizabeth Bjornsen, David Berkoff, J. Troy Blackburn, Hope Davis‐Wilson, Alyssa Evans‐Pickett, Jason R. Franz, Matthew S. Harkey, W. Zachary Horton, Caroline Lisee, Brittney Luc‐Harkey, Amanda E. Munsch, Daniel Nissman, Steven Pfeiffer, Brian Pietrosimone
Journal: Arthritis & Rheumatology (2023)

The objective of this study was to compare the vertical (vGRF), anterior-posterior (apGRF), and medial-lateral (mlGRF) ground reaction force (GRF) profiles throughout the stance phase of gait (1) between individuals 6 to 12 months post-anterior cruciate ligament reconstruction (ACLR) and uninjured matched controls and (2) between ACLR and individuals with differing radiographic severities of knee osteoarthritis (KOA), defined as Kellgren and Lawrence (KL) grades KL2, KL3, and KL4.
Time to address the challenge of difficult to treat psoriatic arthritis: results from an international survey
Authors: Helena Marzo-Ortega, Stephanie Rose Harrison, György Nagy, Pedro M Machado, Dennis G McGonagle, Sibel Zehra Aydin, Raquel Almodovar-González, Wilson Bautista-Molano, Laure Gossec, Ennio Lubrano, Peter Nash, Fernando Pimentel Santos, Enrique R Soriano, Stefan Siebert
Journal: Annals of the Rheumatic Diseases (2023)
A Novel Self‐Pumping Janus Dressing for Promoting Wound Immunomodulation and Diabetic Wound Healing
Authors: Lubin Zhou, Fan Liu, Junyuan You, Bo Zhou, Wenlai Guo, Wenrui Qu, Xiuyan Ren, Guanghui Gao
Journal: Advanced Healthcare Materials (2023)

Self-pumping dressings become one of the optimal solutions for the controlled management of chronic diabetic wound exudate and wound healing. However, present self-pumping dressings are not only prone to breakage of the loose hydrophobic layer but also have cumbersome and complicated preparation steps, which hinder the application of self-pumping dressings in diabetic wound treatment. Herein, a novel self-pumping structure of superabsorbent Janus dressing is designed to improve the strength of the hydrophobic layer and promote diabetic wound healing. The Janus dressing consists of a hydrophobic layer with a drainage agent (drainage layer) and a fluffy 3D nanofiber cotton (absorbent layer). Regardless of the thickness of the drainage layer, the drainage agent in the drainage layer provides the fluid to penetrate the drainage layer to the absorbent layer for unidirectional fluid draining. In design proof, the superabsorbent Janus dressing provides unidirectional drainage of inflammatory exudate and regulation of macrophage polarization, resulting in faster diabetic wound healing than single-layer dressings. Thus, the Janus dressing demonstrates important clinical implications to offer a novel design and preparation strategy for accelerating diabetic wound healing.
18F-FDG PET/CT Versus 18F-FAPI PET/CT in a Case of Recurrent Malignant Phyllodes Breast Tumor
Authors: Shuqin Jiang, Ming Jiang, Songquan Rao, Jiucen Liang, Rusen Zhang
Journal: Clinical Nuclear Medicine (2023)

Abstract A 52-year-old woman with medical history of surgery for left malignant phyllodes breast tumor found a mass on the left chest 3 months ago. A suspicion of recurrent malignant phyllodes breast tumor was made. The patient was enrolled in the clinical trial of 18 F-FAPI PET/CT in recurrent sarcoma (no. NCT05485792). 18 F-FAPI PET/CT and 18 F-FDG PET/CT were performed, and the images demonstrated intense uptake in a huge mass in the left anterior chest wall. Then the patient underwent extended resection of left chest wall tumor. The tumor proved to be recurrent malignant phyllodes breast tumor pathologically.
Dual‐Targeting Nanovesicles Carrying CSF1/CD47 Identified from Single‐Cell Transcriptomics of Innate Immune Cells in Heart Transplant for Alleviating Acute Rejection
Authors: Zhanxue Xu, Xiaofan Mao, Xingyu Lu, Peilin Shi, Jingping Ye, Xinrui Yang, Qingling Fu, Chao He, Dandan Su, Yichu Nie, Longshan Liu, Changxi Wang, Benjie Zhou, Wei Luo, Fang Cheng, Hongbo Chen
Journal: Advanced Healthcare Materials (2023)

Although immunosuppressive drugs for targeting T cells are the standard of care in acute transplantation rejection, the role of innate immune cells should not be ignored. Here, single-cell RNA sequencing (scRNA-seq) and flow cytometry are performed to reveal the dynamic changes of innate immune cells within the acute rejection time and find a significantly-increased presence of Ly6G- Ly6C+ inflammatory macrophages and decreased presence of neutrophils among all types of immune cells. Next, to further explore potential targets regulating Ly6G- Ly6C+ inflammatory macrophages, scRNA-seq is used to analyze the reciprocal signaling of both neutrophils and macrophages, along with the surface genes of macrophages. It is found that activating colony-stimulating factor 1/ colony-stimulating factor 1 receptor (CSF1/CSF1R) andcluster of differentiation 47/signal regulatory protein α (CD47/SIRPα) signaling may serve as a strategy to relieve Ly6G- Ly6C+ inflammatory macrophage-mediated early graft rejection. To investigate this hypothesis, CSF1/CD47 dual-targeting nanovesicles (NVs) derived from IFN-γ-stimulated induced pluripotent stem cell-derived mesenchymal stem cells ( iPSC-MSCs )are designed and constructed. It is confirmed that CSF1/CD47 NVs synergistically induce the differentiation of Ly6G- Ly6C- M2 inhibitory macrophages by the CSF1/CSF1R pathway, and inhibit the phagocytosis of inflammatory macrophages and inflammatory response by the CD47/SIRPα pathway, ultimately relieving immune rejection. This study highlights the power of dual-targeting CSF1/CD47 NVs as an immunosuppressant against early innate immune responses with the potential for broad clinical applications.
Extramedullary Plasmacytoma of the Retroperitoneum Detected on 18F-FDG PET/CT
Authors: Yan Deng, Ying Deng, Wei Zhang, Xiaoping Lei
Journal: Clinical Nuclear Medicine (2023)

Abstract Solitary retroperitoneal extramedullary plasmacytoma is a rare neoplasm. A 67-year-old man presented with abdominal pain and left leg weakness. Abdominal CT revealed a large mass in the left retroperitoneum, which demonstrated increased metabolic activity on subsequent 18 F-FDG PET/CT imaging. Furthermore, the patient’s serum protein electrophoresis showed positive M-protein results. Pathological examination of the biopsied specimen confirmed the diagnosis of extramedullary plasmacytoma.
Scarlett McNally: We must all change, not just the bad apples
Authors: Scarlett McNally
Journal: BMJ (2023)

A recent report by the Working Party on Sexual Misconduct in Surgery found that 30% of women surgeons surveyed had been sexually assaulted by co-workers. 1 2 In response to the report there have rightly been demands for improved reporting structures and better support after an assault.But we also need prevention.Toxic workplace cultures allow poor behaviours, including sexual misconduct, to flourish.Most of us haven't been explicitly taught how to behave or communicate since school.But we all need to change, and so do some cultures in the NHS.
Cardiovascular Outcomes of α-Blockers vs 5-α Reductase Inhibitors for Benign Prostatic Hyperplasia
Authors: Jiandong Zhang, Chase D. Latour, Oluwasolape Olawore, Virginia Pate, David F. Friedlander, Til Stürmer, Michele Jonsson Funk, Brian C. Jensen
Journal: JAMA Network Open (2023)

Importance The most prescribed class of medications for benign prostatic hyperplasia (BPH) is α-blockers (ABs). However, the cardiovascular safety profile of these medications among patients with BPH is not well understood. Objective To compare the safety of ABs vs 5-α reductase inhibitors (5-ARIs) for risk of adverse cardiovascular outcomes. Design, Setting, and Participants This active comparator, new-user cohort study was conducted using insurance claims data from a 20% random sample of Medicare beneficiaries from 2007 to 2019 to evaluate the 1-year risk of adverse cardiovascular outcomes. Males aged 66 to 90 years were indexed into the cohort at new use of an AB or 5-ARI. Twelve months of continuous enrollment and at least 1 diagnosis code for BPH within 12 months prior to initiation were required. Data were analyzed from January 2007 through December 2019. Exposures Exposure was defined by a qualifying prescription fill for an AB or 5-ARI after at least 12 months without a prescription for these drug classes. Main Outcomes and Measures Follow-up began at a qualified refill for the study drug. Primary study outcomes were hospitalization for heart failure (HF), composite major adverse cardiovascular events (MACE; hospitalization for stroke, myocardial infarction, or death), composite MACE or hospitalization for HF, and death. Inverse probability of treatment and censoring-weighted 1-year risks, risk ratios (RRs), and risk differences (RDs) were estimated for each outcome. Results Among 189 868 older adult males, there were 163 829 patients initiating ABs (mean [SD] age, 74.6 [6.2] years; 579 American Indian or Alaska Native [0.4%], 5890 Asian or Pacific Islander [3.6%], 9179 Black [5.6%], 10 610 Hispanic [6.5%], and 133 510 non-Hispanic White [81.5%]) and 26 039 patients initiating 5-ARIs (mean [SD] age, 75.3 [6.4] years; 76 American Indian or Alaska Native [0.3%], 827 Asian or Pacific Islander [3.2%], 1339 Black [5.1%], 1656 Hispanic [6.4%], and 21 605 non-Hispanic White [83.0%]). ABs compared with 5-ARIs were associated with an increased 1-year risk of MACE (8.95% [95% CI, 8.81%-9.09%] vs 8.32% [95% CI, 7.92%-8.72%]; RR = 1.08 [95% CI, 1.02-1.13]; RD per 1000 individuals = 6.26 [95% CI, 2.15-10.37]), composite MACE and HF (RR = 1.07; [95% CI, 1.03-1.12]; RD per 1000 individuals = 7.40 [95% CI, 2.88-11.93 ]), and death (RR = 1.07; [95% CI, 1.01-1.14]; RD per 1000 individuals = 3.85 [95% CI, 0.40-7.29]). There was no difference in risk for HF hospitalization alone. Conclusions and Relevance These results suggest that ABs may be associated with an increased risk of adverse cardiovascular outcomes compared with 5-ARIs. If replicated with more detailed confounder data, these results may have important public health implications given these medications’ widespread use.
Repurposing AZD5438 and Dabrafenib for Cisplatin-Induced AKI
Authors: Chithra K. Pushpan, Daniel F. Kresock, Matthew A. Ingersoll, Richard D. Lutze, Darby L. Keirns, William J. Hunter, Khalid Bashir, Tal Teitz
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement To combat both untoward effects of nephrotoxicity and ototoxicity in cisplatin-treated patients, two potential therapeutic oral anticancer drugs AZD5438 and dabrafenib, a phase-2 clinical trial protein kinase CDK2 inhibitor and an US Food and Drug Administration–approved drug BRAF inhibitor, respectively, were tested in an established mouse AKI model. Both drugs have previously been shown to protect significantly against cisplatin-induced hearing loss in mice. Each drug ameliorated cisplatin-induced increases in the serum biomarkers BUN, creatinine, and neutrophil gelatinase-associated lipocalin. Drugs also improved renal histopathology and inflammation, mitigated cell death by pyroptosis and necroptosis, and significantly enhanced overall survival of cisplatin-treated mice. Background Cisplatin is an effective chemotherapy agent for a wide variety of solid tumors, but its use is dose-limited by serious side effects, including AKI and hearing loss. There are no US Food and Drug Administration–approved drugs to treat both side effects. Recently, two anticancer oral drugs, AZD5438 and dabrafenib, were identified as protective against cisplatin-induced hearing loss in mice. We hypothesize that similar cell stress and death pathways are activated in kidney and inner ear cells when exposed to cisplatin and tested whether these drugs alleviate cisplatin-induced AKI. Methods The HK-2 cell line and adult FVB mice were used to measure the protection from cisplatin-induced cell death and AKI by these drugs. Serum markers of kidney injury, BUN, creatinine, and neutrophil gelatinase-associated lipocalin as well as histology of kidneys were analyzed. The levels of markers of kidney cell death, including necroptosis and pyroptosis, pERK, and proliferating cell nuclear antigen, were also examined by Western blotting and immunofluorescence. In addition, CDK2 knockout (KO) mice were used to confirm AZD5438 protective effect is through CDK2 inhibition. Results The drugs reduced cisplatin-induced cell death in the HK-2 cell line and attenuated cisplatin-induced AKI in mice. The drugs reduced serum kidney injury markers, inhibited cell death, and reduced the levels of pERK and proliferating cell nuclear antigen, all of which correlated with prolonged animal survival. CDK2 KO mice were resistant to cisplatin-induced AKI, and AZD5438 conferred no additional protection in the KO mice. Conclusions Cisplatin-induced damage to the inner ear and kidneys shares similar cellular beneficial responses to AZD5438 and dabrafenib, highlighting the potential therapeutic use of these agents to treat both cisplatin-mediated kidney damage and hearing loss.
National Comprehensive Cancer Network Guideline Recommendations of Cancer Drugs With Accelerated Approval
Authors: Edward R. Scheffer Cliff, Rachel S. Rome, Aaron S. Kesselheim, Benjamin N. Rome
Journal: JAMA Network Open (2023)

Importance Many cancer drugs are approved under the US Food and Drug Administration (FDA) accelerated approval pathway based on preliminary evidence. It is unclear how this limited evidence is integrated into the National Comprehensive Cancer Network (NCCN) guidelines, which are common references for clinicians and are used by public and private payers to determine reimbursement for oncology treatments. Objective To analyze the NCCN guidelines’ assessments for cancer drug indications that received FDA accelerated approval compared with cancer drug indications that received FDA regular approval. Design, Setting, and Participants This cross-sectional study analyzes FDA-approved indications for cancer drugs that were granted accelerated approval from program inception in 1992 to June 30, 2022. For each drug, the FDA-approved labeling was reviewed to identify all indications. All analyses were performed at the drug-indication level. Exposure The exposure was FDA regulatory status as of October 2022, including regular approval, accelerated approval, accelerated approval converted to regular approval, and withdrawn accelerated approval. Main Outcomes and Measures The level of evidence and consensus (category 1, 2A, 2B, and 3) and treatment preference (preferred, alternative preferred, other recommended, and useful in certain circumstances) ratings assigned by NCCN committees as of February 2023. Results A total of 315 oncology indications for 100 drugs were analyzed. These indications included 156 (50%) with regular approval, 60 (38%) with accelerated approval, 78 (49%) with accelerated approval that was converted to regular approval, and 21 (13%) with withdrawn accelerated approvals. Among all indications, 105 (33%) were rated by the NCCN as having category 1 evidence, 185 (59%) with category 2A, 6 (2%) with category 2B, and 2 (1%) with category 3 evidence. Compared with indications with regular approval, those with accelerated approval were less frequently assigned category 1 evidence (47% vs 3%; P &amp;amp;lt; .001) and were less often listed as preferred treatment options (58% vs 40%; P = .008). Among the 21 withdrawn accelerated approval indications, 8 (38%) remained in the NCCN guidelines, with most having level 2A evidence ratings. Conclusions and Relevance This study found that cancer drug indications with accelerated approval were less likely to be assigned high-level evidence ratings and preferred status in the NCCN guidelines compared with indications with regular approval; most accelerated and regular approval drugs had low-quality evidence ratings but high levels of consensus among oncologists on NCCN committees. Greater clarity on the thresholds and definitions of evidence levels would make the NCCN guidelines more useful to clinicians, patients, and payers.
Type 2 Diabetes and Colorectal Cancer Risk
Authors: Thomas Lawler, Zoe L. Walts, Mark Steinwandel, Loren Lipworth, Harvey J. Murff, Wei Zheng, Shaneda Warren Andersen
Journal: JAMA Network Open (2023)

Importance Type 2 diabetes and colorectal cancer (CRC) disproportionately burden indviduals of low socioeconomic status and African American race. Although diabetes is an emerging CRC risk factor, associations between diabetes and CRC in these populations are understudied. Objective To determine if diabetes is associated with CRC risk in a cohort representing understudied populations. Design, Setting, and Participants This cohort study uses data from the prospective Southern Community Cohort Study in the US, which recruited from 2002 to 2009 and completed 3 follow-up surveys by 2018. Of about 85 000 participants, 86% enrolled at community health centers, while 14% were enrolled via mail or telephone from the same 12 recruitment states. Participants with less than 2 years of follow-up, previous cancer diagnosis (excluding nonmelanoma skin cancer) at enrollment, missing enrollment diabetes status, diabetes diagnosis before age 30, and without diabetes at enrollment with no follow-up participation were excluded. Data were analyzed from January to September 2023. Exposures Physician-diagnosed diabetes and age at diabetes diagnosis were self-reported via survey at enrollment and 3 follow-ups. Main Outcomes and Measures Diabetes diagnosis was hypothesized to be positively associated with CRC risk before analysis. Incident CRC was assessed via state cancer registry and National Death Index linkage. Hazard ratios and 95% CIs were obtained via Cox proportional hazard models, using time-varying diabetes exposure. Results Among 54 597 participants, the median (IQR) enrollment age was 51 (46-58) years, 34 786 (64%) were female, 36 170 (66%) were African American, and 28 792 (53%) had income less than $15 000 per year. In total, 289 of 25 992 participants with diabetes developed CRC, vs 197 of 28 605 participants without diabetes. Diabetes was associated with increased CRC risk (hazard ratio [HR], 1.47; 95% CI, 1.21-1.79). Greater associations were observed among participants without colonoscopy screening (HR, 2.07; 95% CI, 1.16-3.67) and with smoking history (HR, 1.62; 95% CI, 1.14-2.31), potentially due to cancer screening differences. Greater associations were also observed for participants with recent diabetes diagnoses (diabetes duration &amp;amp;lt;5 years compared with 5-10 years; HR, 2.55; 95% CI, 1.77-3.67), possibly due to recent screening. Conclusions and Relevance In this study where the majority of participants were African American with low socioeconomic status, diabetes was associated with elevated CRC risk, suggesting that diabetes prevention and control may reduce CRC disparities. The association was attenuated for those who completed colonoscopies, highlighting how adverse effects of diabetes-related metabolic dysregulation may be disrupted by preventative screening.
Mg2+ supplementation treats secretory diarrhea in mice by activating calcium-sensing receptor in intestinal epithelial cells
Authors: Livia de Souza Goncalves, Tifany Chu, Riya Master, Parth D. Chhetri, Qi Gao, Onur Cil
Journal: Journal of Clinical Investigation (2023)

Cholera is a global health problem with no targeted therapies. The Ca2+-sensing receptor (CaSR) is a regulator of intestinal ion transport and a therapeutic target for diarrhea, and Ca2+ is considered its main agonist. We found that increasing extracellular Ca2+ had a minimal effect on forskolin-induced Cl- secretion in human intestinal epithelial T84 cells. However, extracellular Mg2+, an often-neglected CaSR agonist, suppressed forskolin-induced Cl- secretion in T84 cells by 65% at physiological levels seen in stool (10 mM). The effect of Mg2+ occurred via the CaSR/Gq signaling that led to cAMP hydrolysis. Mg2+ (10 mM) also suppressed Cl- secretion induced by cholera toxin, heat-stable E. coli enterotoxin, and vasoactive intestinal peptide by 50%. In mouse intestinal closed loops, luminal Mg2+ treatment (20 mM) inhibited cholera toxin-induced fluid accumulation by 40%. In a mouse intestinal perfusion model of cholera, addition of 10 mM Mg2+ to the perfusate reversed net fluid transport from secretion to absorption. These results suggest that Mg2+ is the key CaSR activator in mouse and human intestinal epithelia at physiological levels in stool. Since stool Mg2+ concentrations in patients with cholera are essentially zero, oral Mg2+ supplementation, alone or in an oral rehydration solution, could be a potential therapy for cholera and other cyclic nucleotide-mediated secretory diarrheas.
Single cell-resolved study of advanced murine MASH reveals a homeostatic pericyte signaling module
Authors: Sofie M. Bendixen, Peter R. Jakobsgaard, Daniel Hansen, Kamilla H. Hejn, Mike K. Terkelsen, Frederik A. Bjerre, Annemette P. Thulesen, Niels G. Eriksen, Philip Hallenborg, Yana Geng, Trine V. Dam, Frederik T. Larsen, Charlotte W. Wernberg, Janusa Vijayathurai, Emma A.H. Scott, Ann-Britt Marcher, Sönke Detlefsen, Lars Grøntved, Henrik Dimke, Rebecca Berdeaux, Thomas Q. de Aguiar Vallim, Peter Olinga, Mette M. Lauridsen, Aleksander Krag, Blagoy Blagoev, Kim Ravnskjaer
Journal: Journal of Hepatology (2023)

Background & Aims Metabolic dysfunction-associated steatohepatitis (MASH) is linked to insulin resistance and type II-diabetes and marked by hepatic inflammation, microvascular dysfunction, and fibrosis, impairing liver function and aggravating metabolic derangements. Liver homeostatic interactions disrupted in MASH are still poorly understood. We aimed to elucidate the plasticity and changing interactions of non-parenchymal cells associated with advanced MASH. Methods We characterized a diet-induced mouse model of advanced MASH at single-cell resolution and validated findings by assaying chromatin accessibility, bioimaging of murine and human liver, and by functional experiments in vivo and in vitro. Results The fibrogenic activation of hepatic stellate cells (HSCs) led to deterioration of a signaling module consisting of the bile-acid receptor NR1H4/FXR and HSC-specific GS-protein-coupled receptors (GSPCRs) capable of preserving stellate cell quiescence. Accompanying HSC activation, we further observed the attenuation of HSC Gdf2 expression, and a MASH-associated expansion of a CD207-positive macrophage population likely derived from both incoming monocytes and Kupffer cells. Conclusion We conclude that HSC-expressed NR1H4 and GSPCRs of the healthy liver integrate postprandial cues, which sustain HSC quiescence and through, paracrine signals, overall sinusoidal health. HSC activation in MASH hence not only drives fibrogenesis but may desensitize the hepatic sinusoid to liver homeostatic signals. Impact and Perspectives Homeostatic interactions between hepatic cell types and their deterioration in Metabolic Dysfunction-Associated Steatohepatitis (MASH) are poorly characterized. In our current single cell-resolved study of advanced murine MASH we identified a quiescence-associated hepatic stellate cell-signaling module with potential to preserve normal sinusoid function. As expression levels of its constituents are conserved in the human liver, the signaling module may be amenable to therapeutic stimulation for restoration of sinusoid function in chronic liver disease.